Abstract 4236: PDX-derived organoids (PDXO) are valuable tools to unveil the shortcomings of new anti-cancer drug candidates

Abstract Introduction: Tumor organoids are increasingly being used as predictive preclinical cancer models, as they reflect the original tumor features and patient drug responses. However, systematic comparisons between organoids and traditional 2D cell lines or 3D spheroids are lacking. Method: We established over 30 PDX-derived organoid (PDXO) models with KRAS mutations and tested three inhibitors targeting the KRAS pathway: VS-6766 (RAF/MEK inhibitor), Trametinib (MEK inhibitor), and MRTX1133 (a Phase II drug targeting KRASG12D) against these models. Results: IC50 results indicated that most models responded to treatment. For some cell lines we detected differential drug responses in 2D vs. 3D testing with 3Dspheroids being more sensitive to inhibitors than 2D cell lines (on average ~10 fold). PDXO models exhibited greater individual differences in drug response, with a subset of models demonstrating no sensitivity to MRTX1133. This is consistent with published results showing that some KRASG12D-mutant PDX models were less sensitive to MRTX11331. Similarly, the clinical trial data for the KRASG12C inhibitor Adagrasib revealed distinctions in the response of patients2. Further analysis with WES (whole exome sequencing) and RNA-sequencing identified potential genotypic mutations and differential expressions of signaling pathways related to drug resistance. Subsequent drug combination testing showed that targeting these pathways could enhance the MRTX1133 efficacy in the resistant PDXO models. Summary: Our research confirms that drug testing on organoids predicts responses in mouse models and clinical trials. In combination with multi-omics and bioinformatics analysis, the platform can be used for evaluating drug resistances, identifying new targets, developing new drug combination therapies, and ultimately improving the creation of new cancer therapeutics. Citation Format: Yuhui Wang, Lin Feng, Han Liu, Junwen Zhang, Kaiqiang Hu, Pengwei Pan, Fang He. PDX-derived organoids (PDXO) are valuable tools to unveil the shortcomings of new anti-cancer drug candidates abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4236.